4--o-methylalpinumisoflavone and alpinumisoflavone

Hypoxia is a common feature of solid tumors, and the extent of tumor hypoxia correlates with advanced disease stages and treatment resistance. The transcription factor hypoxia-inducible factor-1 (HIF-1) represents an important tumor-selective molecular target for anticancer drug discovery directed at tumor hypoxia. A natural product chemistry-based approach was employed to discover small molecule inhibitors of HIF-1. Bioassay-guided isolation of an active lipid extract of the tropical legumaceous plant Lonchocarpus glabrescens and structure elucidation afforded two new HIF-1 inhibitors: alpinumisoflavone (compound 1) and 4'-O-methylalpinumisoflavone (compound 2). In human breast tumor T47D cells, compounds 1 and 2 inhibited hypoxia-induced HIF-1 activation with IC(50) values of 5 and 0.6 mum, respectively. At the concentrations that in hibited HIF-1 activation, compound 2 inhibited hypoxic induction of HIF-1 target genes (CDKN1A, GLUT-1, and VEGF), tumor angiogenesis in vitro, cell migration, and chemotaxis. Compound 2 inhibits HIF-1 activation by blocking the induction of nuclear HIF-1alpha protein, the oxygen-regulated subunit that controls HIF-1 activity. Mechanistic studies indicate that, unlike rotenone and other mitochondrial inhibitors, compound 2 represents the first small molecule that inhibits HIF-1 activation by simultaneously suppressing mitochondrial respiration and disrupting protein translation in vitro. This unique mechanism distinguishes compound 2 from other small molecule HIF-1 inhibitors that are simple mitochondrial inhibitors or flavanoid-based protein kinase inhibitors.

Topics: Blotting, Western; Breast Neoplasms; Cell Hypoxia; Cell Movement; Cell Proliferation; Cell Respiration; Cell Survival; Cells, Cultured; Chemotaxis; Cyclin-Dependent Kinase Inhibitor p21; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Fabaceae; Glucose Transporter Type 1; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Isoflavones; Male; Mitochondria; Neovascularization, Pathologic; Oxygen Consumption; Prostatic Neoplasms; Protein Biosynthesis; Umbilical Veins; Vascular Endothelial Growth Factor A; Wound Healing

A methylene chloride soluble fraction of the fruits of Cudrania tricuspidata significantly inhibited the mouse brain monoamine oxidase (MAO). Three known prenylated isoflavones were isolated and identified by activity-guided fractionation. Gancaonin A (1), 4'-O-methylalpinumisoflavone (2), and alpinumisoflavone (3) inhibited MAO activity in a concentration-dependent manner with IC50 values of 19.4, 23.9, and 25.8 microM, respectively. Of these, gancaonin A (1) showed a selective and potent inhibitory effect against MAO-B (IC50 0.8 microM) than MAO-A (IC50 >800 microM). The kinetic analysis using Lineweaver-Burk plots indicated that gancaonin A (1) competitively inhibited MAO-B.

Topics: Animals; Brain; Dose-Response Relationship, Drug; Fruit; Isoflavones; Kinetics; Maclura; Methylene Chloride; Mice; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Plant Extracts; Plants, Medicinal